On January 18, 2019, Bristol-Myers Squibb Company ("Bristol-Myers Squibb") reported that it has entered into a Term Loan Agreement (the "Term Loan Agreement") with the lenders party thereto and Morgan Stanley Senior Funding, Inc., as administrative agent (Filing, 8-K, Bristol-Myers Squibb, JAN 18, 2019, View Source [SID1234532805]). The Term Loan Agreement provides for total term loan commitments in an aggregate principal amount of $8.0 billion and reduces the $33.5 bridge facility commitments previously described in the Current Report on Form 8-K filed by Bristol-Myers Squibb with the Securities and Exchange Commission (the "SEC") on January 4, 2019 (the "January 4 Current Report") by such principal amount. The Term Loan Agreement was entered into in connection with the previously announced proposed merger (the "Merger") of a wholly owned subsidiary of Bristol-Myers Squibb with Celgene Corporation ("Celgene"), pursuant to the Agreement and Plan of Merger, dated as of January 2, 2019 (the "Merger Agreement"), among Bristol-Myers Squibb, Celgene and Burgundy Merger Sub, Inc., a wholly-owned subsidiary of Bristol-Myers Squibb, described in the January 4 Current Report.

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The lenders party to the Term Loan Agreement will be obligated to make loans under the Term Loan Agreement upon the satisfaction or waiver of several limited conditions, including but not limited to completion of the Merger, the non-occurrence of a material adverse effect (as such term is defined in the Term Loan Agreement) on Celgene, the accuracy in all material respects of certain representations and warranties related to both Bristol-Myers Squibb and Celgene, the absence of certain defaults by Bristol-Myers Squibb, the delivery of certain financial statements of Bristol-Myers Squibb and Celgene and other customary conditions to completion more fully set forth in the Term Loan Agreement. The date such limited conditions are satisfied or are waived in accordance with the terms of the Term Loan Credit Agreement and the loans thereunder are funded is referred to herein as the "Closing Date."

The term loan facility under the Term Loan Agreement consists of a $1 billion 364-day tranche, a $4 billion three-year tranche and a $3 billion five-year tranche. Borrowings under the Term Loan Agreement will be unsecured. The term loans are pre-payable without premium or penalty (but subject to breakage costs, if applicable). The term loans under the $1 billion 364-day and the $4 billion three-year tranche do not amortize. The five-year tranche amortizes in equal quarterly amounts equal to (i) 0.0% from after the Closing Date to, and including, the third anniversary of the Closing Date and (ii) 10% per annum from after the third anniversary to, and including, the five-year anniversary of the Closing Date. The $1 billion tranche of the term loan facility will mature and be payable on the 364-day anniversary of the Closing Date. The $4 billion tranche of the term loan facility will mature and be payable on the third anniversary of the Closing Date. The $3 billion tranche of the term loan facility will mature and be payable (to the extent not amortized) on the fifth anniversary of the Closing Date.

At the option of Bristol-Myers Squibb, borrowings under the Term Loan Agreement will bear interest at either a base rate or at the Eurodollar rate, plus, in each case, an applicable margin. The applicable margin will range from (i) with respect to the $1 billion 364-day tranche, 0.0 – 0.125% with respect to base rate borrowings, and 0.75 – 1.125% with respect to Eurodollar rate borrowings, (ii) with respect to the $4 billion three-year tranche, 0.0 – 0.25% with respect to base rate borrowings, and 0.875 – 1.25% with respect to Eurodollar rate borrowings, and (iii) with respect to the $3 billion five-year tranche, 0.0 – 0.375% with respect to base rate borrowings, and 1.00 – 1.375% with respect to Eurodollar rate borrowings in each case, based on the public ratings of Bristol-Myers Squibb’s non-credit enhanced senior unsecured long-term debt, as set forth in the Term Loan Agreement. The base rate will be, for any day, a fluctuating rate per annum equal to the highest of (i) the rate last quoted by The Wall Street Journal as the "Prime Lending Rate" (if more than one rate is published as the Prime Lending Rate, then the highest of such rates), (ii) the Federal Funds effective rate plus 0.5% and (iii) the one-month reserve adjusted Eurodollar Rate plus 1% (provided, that the reserve adjusted Eurodollar Rate shall not be less than zero). The Eurodollar rate will be an annual rate equal to the London Interbank Offered Rate. Pursuant to the base rate option, interest will be calculated on the basis of the actual number of days elapsed in a year of 365 or 366 days and will be payable quarterly in arrears. Alternatively, under the Eurodollar rate option, interest will be determined based on interest periods to be selected by Bristol-Myers Squibb of one, two, three or six months, will be calculated on the basis of the actual number of days elapsed in a year of 360 days and will be payable at the end of each interest period (and at the end of every three months, in the case of interest periods longer than three months).

The Term Loan Agreement contains certain covenants relating to the following subjects: legal existence; business and properties; delivery of financial statements, reports, etc.; maintenance of insurance; obligations and payment of taxes; litigation and other notices; books and records; maintenance of ratings; compliance with laws; limitations on mergers, sales of assets and consolidations; limitations on liens; limitations on sale and leaseback transactions; and sanctions, anti-corruption laws and guaranties.

The Term Loan Agreement also contains certain events of default, limited to nonpayment of principal when due; nonpayment of interest, fees or other amounts after a three business day grace period; material inaccuracy of representations and warranties; violation of covenants (subject, in the case of certain affirmative covenants, to certain grace periods); cross-payment default and cross-acceleration; bankruptcy events; material judgments; change of control; certain ERISA events; and to the extent there are any guarantees of the term facility then in effect, actual or asserted invalidity of such guarantees under the Term Loan Agreement.

The description of the Term Loan Agreement contained in this item 1.01 does not purport to be complete and is qualified in its entirety by reference to the full text of the Term Loan Agreement, a copy of which is filed hereto as Exhibit 10.1 to this Current Report on Form 8-K, and the terms of which are incorporated herein by reference.
The representations, warranties and covenants contained in the Term Loan Agreement were made only for purposes of such agreement and as of the dates specified therein, were solely for the benefit of the parties thereto and may be subject to standards of materiality applicable to the contracting parties that differ from those applicable to investors. Investors should not rely on the representations, warranties and covenants or any descriptions thereof as characterizations of the actual state of facts or condition of Bristol-Myers Squibb and its subsidiaries. Moreover, information concerning the subject matter of any representations, warranties and covenants may change after the dates of the Term Loan Agreement, which subsequent information may or may not be fully reflected in public disclosures by Bristol-Myers Squibb.

Certain of the financial institutions party to the Term Loan Agreement, either directly or through affiliates, have performed, and may in the future perform, various commercial banking, investment banking and other financial advisory services in the ordinary course of business for Bristol-Myers Squibb and in connection with the Merger for which they have received, and will receive, customary fees and commissions.

On January 18, 2019 ImaginAb, Inc., an emerging immuno-oncology imaging company, reported the enrollment of the first patient in the Phase II clinical trial of ImaginAb’s CD8+ T Cell imaging agent (Press release, ImaginAb, JAN 18, 2019, View Source [SID1234532787]). The trial will enroll metastatic cancer patients and will study the correlation of imaging signals observed using ImaginAb’s CD8+ T cell Immuno-PET imaging agent, standard-of-care scans, and immunohistochemistry analysis of CD8 in biopsied tissues. The trial will also measure changes in CD8+ T-cell distribution before and after immuno-oncology therapies. The study is, in part, financially supported by Boehringer Ingelheim and contributes to the aims of the strategic collaboration between ImaginAb and Boehringer Ingelheim to develop ImaginAb’s CD8+ T cell Immuno-PET imaging agent, IAB22M2C.

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IAB22M2C is designed to be used with PET scan technology to non-invasively measure CD8+ T cell tumor infiltrates in patients with cancer, including the identification of changes in CD8+ T cell tumor infiltrates induced by immuno-oncology treatments. This investigational approach has the potential to guide the development of immunomodulatory agents and combinations by assessing whether a patient’s immune system responds to such agents, thereby offering an early prediction of therapeutic response.

"This study is following on the heels of our recently completed Phase I study which showed an excellent safety profile and extremely encouraging preliminary efficacy of our CD8+ T cell Immuno-PET imaging tracer," said Martyn Coombs, CEO of ImaginAb. "We are thrilled to be continuing our collaboration with Boehringer Ingelheim and are looking forward to Phase II data. We have now announced three CD8+ clinical collaborations with pharmaceutical companies, including our collaborations with Nektar Therapeutics and Merck, known as MSD outside the United States and Canada. This progress underscores our belief that our platform has the potential to accelerate clinical development of therapies for cancer patients. We anticipate announcing more collaborations in the near future."

On January 17, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the US Food and Drug Administration (FDA) has accepted the company’s supplemental Biologics License Application (sBLA) for Tecentriq (atezolizumab) in combination with Abraxane [albumin-bound paclitaxel; nab-paclitaxel]) and carboplatin for the initial (first-line) treatment of people with metastatic non-squamous non-small cell lung cancer (NSCLC) who do not have EGFR or ALK genomic tumour aberrations (Press release, Hoffmann-La Roche, JAN 17, 2019, View Source [SID1234532700]). The FDA is expected to make a decision on approval by 2 September 2019.

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"We look forward to working with the FDA in order to bring this Tecentriq-based combination to people with non-squamous non-small cell lung cancer as soon as possible," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Lung cancer is a challenging disease to treat, and this review takes us one step closer towards offering a new treatment option that has shown a clinically meaningful survival benefit in the treatment of this type of disease."

This sBLA is based on results from the Phase III IMpower130 study, which met its co-primary endpoints of overall survival (OS) and progression-free survival (PFS) in the initial treatment of people with metastatic non-squamous NSCLC.

The FDA recently approved Tecentriq in combination with Avastin, paclitaxel and carboplatin (chemotherapy) for the initial treatment of people with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumour aberrations. Tecentriq is also approved by the FDA to treat people with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have disease progression on FDA approved therapy for NSCLC harbouring these aberrations prior to receiving Tecentriq.

About the IMpower130 study
IMpower130 is a Phase III, multicentre, open-label, randomised study evaluating the efficacy and safety of Tecentriq in combination with carboplatin and nab-paclitaxel versus chemotherapy (carboplatin and nab-paclitaxel) alone for chemotherapy-naïve patients with stage IV non-squamous NSCLC. The study enrolled 724 people who were randomised in a 2:1 ratio to receive:

Tecentriq plus nab-paclitaxel and carboplatin (Arm A), or
Nab-paclitaxel and carboplatin (Arm B, control arm)
During the treatment-induction phase, people in Arm A received Tecentriq and carboplatin on day 1 of each 21-day cycle, and nab-paclitaxel on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit, whichever occurred first. People in Arm A received Tecentriq during the maintenance treatment phase until loss of clinical benefit was observed.

During the treatment-induction phase, people in Arm B received carboplatin on day 1 and nab-paclitaxel on days 1, 8 and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression, whichever occurred first. People in Arm B received best supportive care during the maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. People who were consented prior to a protocol revision were given the option to crossover following disease progression to receive Tecentriq as monotherapy until further disease progression.

The co-primary endpoints were:

PFS as determined by the investigator using RECIST v1.1 in people without EGFR or ALK mutations, assessed in the ITT-WT population
OS in the ITT-WT population
The IMpower130 study met its OS and PFS co-primary endpoints as per the study protocol. The interim analysis showed that Tecentriq plus chemotherapy helped people live significantly longer compared with chemotherapy alone (median OS=18.6 versus 13.9 months; hazard ratio [HR]=0.79; 95% CI: 0.64–0.98; p=0.033) in the intention-to-treat wild-type (ITT-WT) population.[1] The Tecentriq-based combination also significantly reduced the risk of disease worsening or death (PFS) compared with chemotherapy alone (median PFS=7.0 versus 5.5 months; HR=0.64; 95% CI: 0.54–0.77; p<0.0001) in the ITT-WT population.[1] Safety for the Tecentriq plus chemotherapy combination appeared consistent with the known safety profiles of the individual medicines, and no new safety signals were identified with the combination. Grade 3-4 treatment-related adverse events (AEs) were reported in 73.2% of people receiving Tecentriq plus chemotherapy compared to 60.3% of people receiving chemotherapy alone.

About NSCLC
Lung cancer is the leading cause of cancer death globally.2 Each year 1.76 million people die as a result of the disease; this translates into more than 4,800 deaths worldwide every day.[2] Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.[3] NSCLC comprises non-squamous and squamous-cell lung cancer, the squamous form of which is characterised by flat cells covering the airway surface when viewed under a microscope.[3]

About Tecentriq
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Currently, Roche has nine Phase III lung cancer studies evaluating Tecentriq alone or in combination with other medicines.

Tecentriq is already approved in the European Union, United States and more than 85 countries for people with previously treated metastatic NSCLC and for certain types of untreated or previously treated metastatic urothelial carcinoma (mUC). Tecentriq was also recently approved in the United States for the initial treatment of people with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumour aberrations.

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients

On January 17, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) reported that it has successfully completed the first module of its previously announced research and option agreement with Astellas Pharma Inc. Within the collaboration, the Company is using its Actinium Warhead Enabling (AWE) Platform to conjugate and label select Astellas targeting agents with the potent actinium-225 (Ac-225) payload (Press release, Actinium Pharmaceuticals, JAN 17, 2019, View Source [SID1234532701]).

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"This collaboration represents Actinium and Astellas’ shared commitment to employ cutting-edge technology in the research of new drug candidates for patients. Therefore, we are delighted that Astellas has opted to progress our ground-breaking collaborative research activities to the next stage of research," said Dr. Dale Ludwig, Actinium’s Chief Scientific Officer. "I am very pleased with the results we have generated in our efforts with Astellas to date, which I believe showcase the capabilities of our AWE Platform Technology. My team and I are excited to execute the next module of the collaboration and are optimistic that we will continue to move the program forward."

Since launching its AWE Program in November 2017, Actinium has achieved a number of milestones including:

Appointed Dr. Dale Ludwig, a leading antibody therapeutics and antibody conjugate expert, as Chief Scientific Officer
Presented positive data at ASH (Free ASH Whitepaper) 2017 demonstrating the superior in vitro cell killing properties of Ac-225 labeled daratumumab or Darzalex, Johnson & Johnson’s blockbuster CD38 targeting therapy for multiple myeloma
Presented additional positive data from in vivo animal studies at AACR (Free AACR Whitepaper) 2018 demonstrating enhanced tumor control and survival with Ac-225 labeled daratumumab
Signed collaborative research and option agreement with Astellas
Actinium’s Chairman and Chief Executive Officer Sandesh Seth added, "Actinium’s AWE technology platform encompasses not only our Ac-225 payload but also our intellectual property, know-how, clinical experience, and exoskeleton of a commercial supply chain that uniquely positions us in the industry. The strong execution of this collaboration thus far showcases Actinium’s expanded R&D capabilities that give us great excitement for what we can accomplish in the future with our team and technology. Combined with the continued clinical progress across our pipeline, particularly our pivotal Phase 3 trial for Iomab-B and expansion of our CD33 program into targeted conditioning and new disease indications, we are motivated to capitalize on the significant opportunities that lie ahead of us."

About Actinium Warhead Enabling Platform Technology

The Actinium Warhead Enabling (AWE) Program has at its centerpiece the AWE Platform Technology. The Company’s proprietary AWE Platform Technology is supported by intellectual property and know-how that enables the creation of Actinium-225 (Ac-225) Radio-Conjugates (ARCs) wherein a biomolecular targeting agent is stably labeled with the powerful Ac-225 payload to enhance targeted cell killing. The AWE Platform is protected by intellectual property covering the use of the "gold standard" chelator DOTA, and any conceivable derivative thereof. Additionally, Actinium holds intellectual property protection covering methods of chelation or labeling of the targeting agent with Ac-225, including newer next-generation methodologies for chelation of Ac-225.

The AWE Program is structured to provide the opportunity for partners or collaborators to derive maximum value from a collaboration by leveraging Actinium’s extensive technical know-how, access to its ARC drug development infrastructure and to its underlying AWE Platform Technology. The AWE Program provides a partner or collaborator with access to Actinium’s knowledge bank and infrastructure allowing collaborators to benefit from accelerated development timelines for its ARCs.

To learn more about the AWE Technology Platform or the AWE Program please contact Eileen Geoghegan, Ph.D., at [email protected].

On January 17, 2019 Nicox SA (Euronext Paris: FR0013018124, COX), an international ophthalmology company, reported the Q4 2018 operational highlights, revenue and cash position for Nicox and its subsidiaries (the "Nicox Group"), as well as key expected milestones in 2019 (Press release, NicOx, JAN 17, 2019, View Source [SID1234532702]).

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Key Upcoming Milestones
NCX 4251 IND: The Investigational New Drug (IND) for NCX 4251 to enable a Phase 2 clinical study in patients with acute exacerbations of blepharitis is on track.

ZERVIATE launch: The commercial launch of ZERVIATETM (cetirizine ophthalmic solution), 0.24% in the U.S. is now planned by our partner Eyevance Pharmaceuticals for summer instead of spring of this year. Nicox is eligible for up to $3 million of a potential future milestone payment from Eyevance related to certain regulatory and near-term manufacturing objectives.

NCX 470 Phase 2 results: The top-line data from the NCX 470 Phase 2 clinical study for the lowering of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension is expected on time in the second half of this year.

Fourth Quarter 2018 and Recent Operational Highlights
The total number of prescriptions for VYZULTA in the U.S. in the fourth quarter of 2018 increased by 47% compared to the third quarter 20181.

On January 8, 2019 we announced that we reached the 50% patient enrollment threshold of our multicenter, U.S. Phase 2 clinical study evaluating our lead product candidate, NCX 470, ahead of schedule. NCX 470 is a novel, second-generation nitric oxide (NO)-donating prostaglandin analog for the lowering of IOP in patients with open-angle glaucoma or ocular hypertension that has demonstrated 2 to 3 mmHg superior IOP lowering vs. the U.S. market leader LUMIGAN in head-to-head preclinical evaluations.

Also in January, our global partner, Bausch + Lomb, a leading global eye health company and wholly owned subsidiary of Bausch Health Companies, Inc., received approval in Canada of VYZULTA (latanoprostene bunod ophthalmic solution), 0.024%. VYZULTA is indicated for the lowering of IOP in patients with open-angle glaucoma or ocular hypertension.

In December 2018, we announced the focusing of our research activities on topical NO-donating new chemical entities combining two mechanisms of action for lowering of IOP and also the signature of a research collaboration with Novaliq GmbH for the development of novel topical ophthalmic formulations of our NO-donating phosphodiesterase-5 (PDE5) inhibitors based on Novaliq’s water-free enabling EyeSol technology.

Also in December 2018, we entered into an exclusive license agreement with Ocumension Therapeutics for the development and commercialization of NCX 470 in the Chinese market. Ocumension Therapeutics is an ophthalmology company funded by 6 Dimensions Capital, one of the leading global healthcare investment funds, formed by the merger of Wuxi Healthcare Ventures and Frontline BioVentures.

Fourth Quarter 2018 Financial Highlights
As of December 31, 2018, the Nicox Group had cash and cash equivalents of €22.0 million as compared with €25.7 million at September 30, 2018 and €41.4 million at December 31, 2017. Net revenue2 for the fourth quarter of 2018 was €3.3 million, which consists of the upfront payment from Ocumension for NCX 470 for the Chinese market and royalties on fourth quarter 2018 sales of VYZULTA by global partner Bausch + Lomb, after deduction of royalty payments due by Nicox. As a comparison, the Nicox Group net revenue2 in the fourth quarter of 2017 was €2.3 million, corresponding to the payment from Bausch + Lomb of the U.S. FDA approval milestone for VYZULTA, and the royalty revenue following its launch in December 2017. Under the new plan for the launch of ZERVIATE in the U.S. announced above, Nicox will no longer receive the $1 million milestone payment associated with the delivery of commercial product to Eyevance but remains eligible for up to $3 million of a potential future milestone payment related to certain regulatory acceptance provisions and certain near term manufacturing objectives.